KFDA Inspection Program
for Quality and Compliance
Efforts
Young-Ok Kim
Clinical Trials Management Div.
Korea Food and Drug Administration
CONTENTS
1
Contents
Drug Information Association
Introduction
2
Regulatory basis for clinical trials
in Korea
3
KFDA’s inspection (Clinical trials)
4
2011 inspection plan
5
Strengthen the competitiveness of
clinical trials
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1. INTRODUCTION
INTRODUCTION
Drug Information Association
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KOREA FOOD AND DRUG ADMINISTRATION
www.kfda.go.kr
Promoting the public health by ensuring
the safety and efficacy of foods,
pharmaceuticals, medical devices and
cosmetics, and supporting the
development of the food and
pharmaceutical industries.
The government
agency committed to
protecting
consumers and
promoting the public
health
Strengthening clinical trial management
Mission
Protect and improve national civil health through enhancement of
management system and strengthening clinical trial policies
Vision
Construct highly globalized level of clinical trial infrastructure and
regulation-advanced country
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KFDA Organization (Apr. 2009)
Commissioner
Spokesperson
National Institute of Food and
Drug Safety Evaluation
Deputy
Commissioner
6 Regional KFDA Offices
Criminal Investigation
Office
Planning &
Coordination
Risk Prevention
Policy Bureau
Risk Prevention
Policy Div.
Food Safety
Bureau
Audit & Inspection
Office
Pharmaceutical
Safety Bureau
Drug Evaluation
Department
Biopharmaceuticals
& Herbal Medicine
Bureau
Medical Device
Safety Bureau
Biopharmaceuticals
Herbal Medicine
Evaluation Dept.
Medical Device
Evaluation Dept.
Risk Information
Div.
Narcotic Control
Div.
Biopharmaceutical
Policy Div.
Medical Device
Policy Div.
Laboratory Audit
& Policy Div.
Pharmaceutical
Quality Div.
Herbal Medicine
Policy Div.
Medical Device
Management Div.
Clinical Trials
Management Div.
Pharmaceutical
Management Div.
Cosmetics Policy
Div.
Medical Device
Quality Div.
General Services
Division
Pharmaceutical
Safety Policy Div
Drug Information Association
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Clinical Trials under control of KFDA
Accreditation
Inspection
Reports
Approval
Adverse
events
KFDA
Drugs
Biologics/Herbal
Medicines
Medical Devices
- Phase 0
- Phase 1 to 3
- Phase 4
- IIT
-Emergency use
- Phase 0
- Phase 1 to 3
- Phase 4
- IIT
- Emergency use
- Clinical trials
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Health functional
food/Functional
cosmetics
- Test for humans
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IND Approval in Korea
KFDA database
250
229
200
184
148
150
113
100
95
76
90
50
58
20
2
0
202
216
1
2001
198
210
National
Series
134
110
1Multinational
108
58
15
2002
Drug Information Association
2003
2004
2005
2006
2007
www.diahome.org
2008
2009
2010
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2. Regulatory Basis of Clinical Trials in Korea
REGULATORY BASIS FOR
CLINICAL TRIALS IN KOREA
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Regulatory Infrastructure
Regulatory hierarchy of clinical trial
Pharmaceutical Affairs Law
(Art 34)
Medical Device Law
(Art 10)
Enforcement Regulation of
Pharmaceutical Affairs Law
(Art 31, 32, 33, 34)
Enforcement Regulation of
Medical Device Law
(Art 12 & 13)
- Guidance for GCP
- Guidance for INDs
- Guidance for Accredited
Clinical Institutes
- Guidance for GCP
- Guidance for INDs
- Guidance for Accredited
Clinical Institutes
 Continuous effort for legalization to support harmonization of clinical related
regulations to international standards since KFDA formed in 1998
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Milestone of KGCP
1987 Establishment of KGCP (recommendation)
1995 Requirement for compliance of KGCP
1999
Adoption of the Bridging Concept (E5)
2000 Harmonized with ICH guideline E6
Establishment of Pharmaceutical Act Article 26-4
(‘07. 4. 11 changed to Article 34)
- protect the rights and safety of subjects
- clarify the responsibility of investigator
- reinforce the function of IRB
2002 Introduction of IND
- Separation between developmental clinical stage and commercial product
approval, IND and NDA
- Participation in multinational study at any stages
2006 KFDA Clinical management team establishment
2007 Management of joint IRB for multi-site clinical trial
2010 Shortened review period for phase 1 clinical trials (healthy
volunteer)
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Overview of Clinical Trials
Principal Investigator
Adverse-Event Reports
ㆍWrites Study Report
ㆍSelects Study Subjects
Auditor
Investigator
Written Informed Consent
Sponsor
ㆍProtocol
ㆍPreclinical Studies
ㆍCompensation
ㆍStudy Monitoring
ㆍData Audit
Protocol
Submission
AdverseEvent(SUSAR
) reports
Protocol Submission
Contract
ㆍStudy Report
ㆍAdverse-Event Reports
Patient
Director of Investigational Site
ㆍIRB
ㆍEstablishment of SOPs
ㆍCreate Administrative Office
ㆍSelect Administrator
ㆍProtect Patients’ Rights
ㆍMaintain Clinical Trial records
IRB
Inspection
Inspection
KFDA
ㆍProtocol approval
ㆍInspection
ㆍInstitution accreditation
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Overview of Investigator initiated Clinical Trials
Principal Investigator
Adverse-Event Reports
ㆍWrites Study Report
ㆍSelects Study Subjects
ㆍCompensation
ㆍStudy Monitoring
ㆍData Audit
Provider
Investigator
Drug / Medical device
ㆍStudy Report
ㆍAdverse-Event Reports
• Protocol Submission
Protocol Submission
Adverse-Event
Reports
Auditor
Written Informed
Consent
Patient
Director of Investigational Site
ㆍIRB
ㆍEstablishment of SOPs
ㆍCreate Administrative Office
ㆍSelect Administrator
ㆍProtect Patients’ Rights
ㆍ Maintain Clinical Trial records
IRB
Inspection
KFDA
- Protocol approval
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Guideline on Accredited Clinical Institutes
effective since 1997 (drug) & 2006 (medical device)
• Aim is to assure the quality of clinical trials according to the
requirements and to qualify clinical institutes since 1997(drugs) &
2006(medical devices)
• What are necessary to be accredited?
– Appropriate facilities and equipments
– Pool of personnel to support the clinical study
– Pertinent IRB structure and activities
– Educational program (KGCP)
– Infrastructure for the clinical trial management
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3. KFDA’s Inspections
KFDA’S INSPECTIONS
(CLINICAL TRIALS)
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Objectives of Inspection
• KFDA inspects sponsors and accredited institutions :
- To protect the rights, safety, and welfare of subjects involved in clinical trials
in Korea
- To verify the integrity and reliability of clinical trial data submitted to KFDA in
support of research/NDA
- To ensure full compliance with the protocol and the regulations, guidelines
and standard operating procedures of clinical trials
• Scope of inspection
- Sites : Clinical Investigator, IRB etc
- Sponsors : Contract Research Organization (if applicable), Monitors etc
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KFDA Inspection
• Inspection type
- Scheduled(Regular) inspection
- Unscheduled(Directed) inspection – for-cause
• Inspection strategy
- Inspection of on-going and completed clinical trials
- Selection of trials based on the risk assessment process and IIT
–
–
–
–
–
–
–
Development phase
Product type (NCE, Recombinant product, Cell therapy, gene therapy, others)
Complexity of the trial design
Subject enrollment
Therapeutic indication or area
Study population (pediatric, other vulnerable, general)
Serious unexpected adverse drug reaction at the clinical trial site
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Inspection Type
<Regular Inspection>
Target
• All Sponsors
• All accredited
clinical institutes
('07: number of 70)
('08: number of 43)
('09: number of 35)
Drug Information Association
Inspectors
• More than two
inspectors in
one team
Contents
• Fulfillment of
overall
institutional
management in
clinical trials
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Period
• One institute,
One team,
No more than 5
days
(personnel and
time can be
appropriately
changed when
required)
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Inspection Type
<Directed Inspection>
Enforcement regulation of PAL Art 32 / MDL Art 13
and KGCP compliance inspections
Annual report
- First subject registry
- Annual report
related to
progression of
clinical trial
- Termination
report
Drug Information Association
Safety report
- SAE reports
Individual SUSAR
e.g. Death etc.
Completion report
- Reliability
of final report
submitted to the
KFDA in support
of NDA
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Etc
- Civil complaint
- Confirmation
of process
related to take-back
and discard of IMP
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Inspection Process
Prior to an Inspection
During an Inspection
After an Inspection
2 weeks ~ 10 days
1 ~ 5 days
2 weeks
Preparation
Progress
Close
Debriefing
Follow-up
 communicate
 summarize  classify the
inspectional
and report
findings into
issues and

review
of
findings
participate in the inspection)
categories
observations
background
 notify a post send an official notice
with site staff
materials (e.g.,
inspectional
 obtain a list of IRBstudy protocol,  documents full
correspondence
informed consent narrative
approved protocol
reporting of any
(Warning Letter
documents,
deviations
or Notice etc)
CRF)
found
during
 interview
inspection
 arrange an inspection  Inspect
facilities
(if site personnel plan to
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Inspection Process - Preparation
• Preparation
– The ‘Annual inspection plan’ is developed and finalized by KFDA
– The inspection dates are arranged and confirmed with the inspectee
– A ‘Notice of inspection’ is sent to the inspectee of the site to be
inspected within 10 days prior to the proposed date(s) of site inspection
– The inspectee should submit a ‘List of approved protocol by IRB’ to
KFDA within 5 days of receipt of the Notice of inspection
- To select the studies and request relating documents for inspection
– Check-list for inspection on investigators, IRBs and sponsors have
been published to guide the related stakeholders for preparation of
KGCP inspection
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Inspection Process – During Inspection
• During Inspection
–
Opening Meeting with key site staff
– Facility Tour
- Visit drug storage & laboratory & archiving room etc
– Document Review
- Study files for essential documents, informed consent documents
- Data in source documents and CRF
- Drug accountability
- Monitoring visit reports
- Documents related to Laboratory
– Interview with study staff and site personnel
– Check the roles and responsibilities of study staff
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Inspection Process – During Inspection
• During Inspection
– Closing meeting after inspection
- Thank site staff for their cooperation and time for this inspection
- Explain what was reviewed during the inspection
- Explain positive aspects of study conduct at the site
- Discuss identified issues and findings during inspection
- Explain corrective actions on significant findings and
- Make an agreement with study staff
- Final report and conclude the inspection
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Inspection Process – Follow-up
• Follow-up
– A ‘Inspection report’ of the finding is issued to inspectee within 2 weeks
after inspection
– The inspectee should submit the ‘Corrective Action and Preventive
Action Plan’ to KFDA within 30 days of receipt of the site inspection
report
– Once the ‘Corrective Action and Preventive Action Plan’ is deemed to be
adequate, a site inspection will be closed. Appropriate action will be
taken if non-compliance is detected
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Classification of inspection findings
• Violation (Critical)
– A significant issue that poses unacceptable risks
- Conditions, practices or processes that adversely affect the rights, safety or well being of
the subjects and/or the quality and integrity of data
- Immediate realization of importance of the problem and pertinent action is required to
solve such issue
- Take an administrative measure according to the Pharmaceutical affairs Law if necessary
• Correction (Major)
– An issue that poses or has the potential to pose high risks
- Conditions, practices or processes that might adversely affect the rights, safety or well
being of the subjects and/or the quality and integrity of data
- Realization of the problem and pertinent action is required to solve such issue
- Corrective actions (Supplement materials) are requested to be submitted to KFDA
- Additional inspection is not necessary once the requested documents are fully submitted
(e.g., pictures and/or source documents)
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Classification of inspection findings
• Caution (Minor)
– An issue that poses or has the potential to pose moderate risks
- Conditions, practices or processes that would not be expected to adversely affect the
rights, safety or well being of the subjects and/or the quality and integrity of data
- Realization of the problem is required to be done
- Point out letter is issued to inspectee to instruct how to improve quality and/or reduce the
potential of deviation to occur in the future
• Recommendations
– The observations that might raise suggestions on how to improve quality
and/or reduce the potential of deviation to occur in the future
- Proceed without further action
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Classification of inspection findings - Actions
• An informational letter
- Consists of deviations and the relating statutes and regulations. Voluntary
corrective action is necessary. Occasionally, such letter requests response
from the IRB
• A warning letter
- Consists of serious deviations and the relating statutes and regulations. A
warning letter generally requests prompt corrective actions and also a
formal written responses to KFDA
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4. 2011 Inspections
2011 INSPECTION PLAN
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2011 Inspection Plan - Objectives
•
•
Establish standard criteria for inspection results open to public
Improve reliability of inspection quality
– Establish inspection SOP for clinical trial inspection
•
Construct a voluntary safety management system
– Open the information of inspection(date and plan) to public for institutions to
prepare all the documents to be inspected
– Establish Inspection Q&A
– Itinerant education
– Establish voluntary inspection SOP for institutions
•
Strengthen the subject protection by providing accurate information to
the subjects
– Inspect ICF and information to trial subjects
– Inspect IRB approval for subject advertisement before conducting clinical
trials
– Inspect labeling of investigational drugs
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2011 Inspection Plan - Targets
• Targets
– Regular(scheduled) inspections
• Accredited clinical trial institutions
– Directed(unscheduled) inspections
• Sponsors, accredited clinical trial Institutions
– Voluntary inspection
• Initiated and performed by accredited clinical trial institutions
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2011 Inspection Plan – Regular Inspection
• Regular(scheduled) Inspection
• Triennial/each institution
• 62 accredited clinical trial institutions
– 58 institutions accredited for drugs
– 27 institutions accredited for medical devices
– 23 institutions accredited for both drugs and medical devices
• Inclusion criteria
– 22 institutions – have not been inspected so far
– 3 institutions – have not been inspected due to no history of conducting clinical
trials
• Exclusion criteria
– 55 institutions inspected in ’09, ’10
– 16 institutions inspected in ‘09, ’10 related to the final report submitted for NDA
– Institutions conducting no clinical trials since last inspection
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2011 Inspection Plan – Directed Inspection
• Directed(unscheduled) Inspection
• Unexpected safety report
– SUSAR report (e.g. death case etc.)
– Issues related to safety concerns
• Complaints
• Sponsors submit NDA along with final report of clinical trials
– Request from NDA review division
– Targets both sponsors and institutions
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5. Strengthen the Competitiveness of Clinical Trials
STRENGTHEN THE
COMPETITIVENESS OF
CLINICAL TRIALS
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5 main ‘Issues and tasks’ of ‘2020 Clinical Future
Creation Planning Group’
Strengthen the
regulatory
competitiveness
Establish
strategic plans
Strengthen the
for medical
capability of
devices clinical
trials
clinical trials
2020 Clinical
development
Future Creation
Planning Group
Drug Information Association
Enhance the
Strengthen the
communication
safety protection
system of clinical
system of clinical
trials
trials
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New KFDA Office in Osong Healthcare
Administration Town
We are in Osong Health
• Click
to edit Master text styles
Administration Town
– Second level
• Third level
– Fourth level
» Fifth level
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THANK YOU FOR YOUR
ATTENTION
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